Though the use of chemotherapy and early detection methods have greatly increased survival rates for women with Stage I-III breast cancer, this progress is threatened by a significant increase in cardiovascular (CV) events for survivors. Over 35% of women experience CV injury, left ventricular (LV) dysfunction, exercise intolerance, or fatigue after receipt of adjuvant chemotherapy (Adj-C) for Stage I-III breast cancer. In addition, CV events are the leading cause of morbidity and mortality for those surviving 5 to 8 years after their breast cancer diagnosis. Currently, little is understood about te origins of CV dysfunction, exercise intolerance, or fatigue in these women, and risk prediction algorithms for CV events do not incorporate breast cancer treatment in their models. We propose a study of baseline and serial longitudinal measures that will determine the influence of Adj-C with and without concomitant radiation treatment on 3 general categories: (1) CV function, (2) exercise capacity and fatigue, and (3) future development of CV events in a cohort of 1,000 women (840 with Stage I-III Breast Cancer and 160 healthy comparators). We also seek to answer questions about the relationship of alterations in LV and aortic function, what demographic risk factors and changes in serum biomarkers precede LV dysfunction, and if risk factor prediction models forecast development of CV events in the same cohort. Our longitudinal study design accounts for pre-existing and dynamic changes in risk factors during receipt of Adj-C and assesses subsequent CV events. This study has secured robust financial and infrastructure support through the Wake Forest NCI Community Oncology Research Program. This partnership reduces the overall cost of the current proposal by funding enrollment, staff reimbursement, regulatory oversight, study database development, echocardiograms, and an active surveillance program to ascertain the occurrence of CV events. This will be the first epidemiologic cohort study designed to fully characterize the time course and define the correlates of subclinical CV dysfunction, exercise intolerance, fatigue and CV events in women treated with Adj-C for breast cancer. A study of this magnitude is important to assess a variety of subjects so that the scientific community may better understand who is at risk and how we can prevent future CV damage. By enrolling patients in community hospitals and utilizing the unique expertise of each Co-Investigator, this study can capture the data needed to make such predictions. The immediate impact of this research will reduce the gaps in knowledge that prevent treatment design and generate risk prediction algorithms to avert CV events in breast cancer survivors. New knowledge from this study will quantify the risk of developing subclinical CV disease and exercise intolerance in this population, identify potential mechanisms, and inform future study development to reduce CV disease and improve overall survival in women with breast cancer.